Fosaprepitant, a prodrug of aprepitant is chemically known as [3-[[(2R,3S)-2-[(1R)-[3,5-bis(trifluoromethyl)phenyl]ethoxyl]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl] phosphoric acid. The N-methyl-D-glucamine salt of fosaprepitant is approved for the treatment of emesis, nausea, cancer therapy toxicity and is available in the market as EMEND® in the US and as IVEMEND® in Europe. Fosaprepitant dimeglumine is structurally represented by following formula I,

Fosaprepitant, a phosphorylated aprepitant, when administered intravenously is rapidly converted to aprepitant, which is a substance P/neurokinin 1 (NK1) receptor antagonist. Emend® is used together with other medications to prevent nausea and vomiting that may be caused by surgery or cancer chemotherapy.
Fosaprepitant and its salts are disclosed in U.S. Pat. No. 5,691,336, which further discloses a process for manufacturing these compounds. The process for preparation of fosaprepitant dimeglumine disclosed in said patent involves two steps, which are schematically presented herein:

According to the US'336 Patent the process for preparation of fosaprepitant dimeglumine involves reaction of aprepitant with tetrabenzyl pyrophosphate using sodium bis(trimethylsilyl)amide (NaHMDS) as a base in the presence of THF as a solvent to obtain crude fosaprepitant dibenzyl ester. This crude fosaprepitant dibenzyl ester obtained is then treated with N-methyl-D-glucamine and Pd/C in the presence of methanol as a solvent to obtain fosaprepitant dimeglumine.
The article, Journal of Medicinal Chemistry, 2000, vol. 43, page no. 1234-1241 by Merck Research Laboratories describes in the preparation example of compound 4 that, the compound 4 is isolated as an oil after three chromatographic runs. However, the article does not disclose the purity of compound 4 achieved after three chromatographic runs.
U.S. Pat. No. 7,807,829 discloses monobenzyl fosaprepitant and its preparation method from aprepitant. The patent teaches that dibenzyl phosphoramidate compound (fosaprepitant dibenzyl ester) is very unstable and is present as an amorphous material, therefore the inventors of said patent converted unstable fosaprepitant dibenzyl ester to stable monobenzyl fosaprepitant.
U.S. Pat. No. 8,623,844 describes a process for preparation of isolated solid crystalline fosaprepitant dibenzyl ester from crude fosaprepitant dibenzyl ester. The process involves obtaining a solution of fosaprepitant dibenzyl ester in a solvent such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tertiary butyl acetate or mixture of solvents; followed by addition of an anti-solvent such as n-pentane, n-hexane, n-heptane, cyclohexane to recover fosaprepitant dibenzyl ester as a crystalline solid. The isolated solid crystalline fosaprepitant dibenzyl ester is of 93.74% purity and contains unknown impurities to an extent of 3.83%. The fosaprepitant dimeglumine prepared from said isolated solid crystalline fosaprepitant dibenzyl ester is of 94.5% purity and the purity of fosaprepitant dimeglumine after additional step of purification is enhanced to 99.76%.
Indian Patent Application No. 2188/CHE/2011 describes an improved process for preparation of fosaprepitant dimeglumine and its intermediate fosaprepitant dibenzyl ester. The process also teaches preparation of co-crystal of fosaprepitant dibenzyl ester with sodium chloride. However, the purity of fosaprepitant dibenzyl ester prepared using said process is not reported in the IN'2188 application. Further, the fosaprepitant dimeglumine prepared using said improved process has purity of at least about 97.1%, which is not a pharmaceutically acceptable grade purity of fosaprepitant dimeglumine. Moreover, the improved process disclosed in IN'2188 application is very lengthy, tedious and involves use of thiophenol resin in the preparation process, which may result in the presence of sulfur content in the fosaprepitant dimeglumine.
The API, fosaprepitant dimeglumine is a highly sensitive moiety and multiple purifications to achieve pharmaceutically acceptable grade purity leads to degradation of fosaprepitant dimeglumine to aprepitant. Therefore, there is a need to prepare highly pure fosaprepitant dibenzyl ester and then convert it to fosaprepitant dimeglumine in order to achieve pharmaceutically acceptable grade purity.
The afore discussed prior art references provide processes for the preparation of fosaprepitant dibenzyl ester and its conversion to fosaprepitant dimeglumine involves either chromatographic purification of fosaprepitant dibenzyl ester oil or isolation of solid crystalline fosaprepitant dibenzyl ester. However in case of column chromatographic purification of fosaprepitant dibenzyl ester oil, the purification involves three chromatographic runs, which is tedious, lengthy and commercially non-feasible process. Further, the non-disclosure of purity of fosaprepitant dibenzyl ester after three chromatographic runs leads to an uncertainty.
Although, U.S. Pat. No. 8,623,844 teaches isolation of solid crystalline fosaprepitant dibenzyl ester, the isolated fosaprepitant dibenzyl ester is unstable and highly hygroscopic in nature and even slight exposure to air will degrade fosaprepitant dibenzyl ester to fosaprepitant monobenzyl ester and/or aprepitant, therefore the fosaprepitant dibenzyl ester obtained according to US'844 patent cannot be stored. Thus, the said process is commercially non-viable. Further, the purity of fosaprepitant dibenzyl ester and its converted fosaprepitant dimeglumine, without additional step of purification is 94.5%, which is not of pharmaceutically acceptable grade.
Thus, there is a need to develop a robust process for preparation of highly unstable fosaprepitant dibenzyl ester and its conversion to fosaprepitant dimeglumine, which is industrially acceptable, commercially viable and provides purity of pharmaceutically acceptable grade, without any additional step of purification.